Reduction of thebaine

ABSTRACT

A PROCESS FOR THE PREPARATION OF 8:14-DIHYDROTHEBAINE FROM THEBAINE, IN WHICH THE THEBAINE IS REDUCED BY HEATING IT WITH AT LEAST ONE OF THE THERMALLY DECOMPOSABLE COMPOUNDS SELECTED FRON AL ARYL OR SUBSTITUTED ALKYL SULPHONIC ACID HYDRAZIDE, AN ALKYL OR SUBSTITUTED ALKYL SULPHONIC ACID HYDRAZID, AN ARALKYL OR SUBSTITUTED ARALKYL SULPHONIC ACID HYDRAZIDE OR DISODIUM AZODICARBOXYLATE, PROVIDED THAT WHEN DISODIUM AZODICARBOXYLATE IS USED, A PROTON SUPPLYING SUBSTANCE IS PRESENT. THE 8:14-DIHYDROTHEBAINE MAY BE HYDROLYZED TO DIHYDROCODEINONE.

United States Patent 01 hoe 3,812,132 Patented May 21, 1974 3,812,132 REDUCTION OF THEBAINE Edward Leon Grew and Alastair Agnew Robertson, Edinburgh, Scotland, assignors to Macfarlan Smith Limited, Edinburgh, Scotland No Drawing. Filed Dec. 2, 1971, Ser. No. 204,298 Claims priority, application (gala; Britain, Dec. 11, 1970,

9 Int. Cl. C07d 43/28 US. Cl. 260-285 12 Claims ABSTRACT OF THE DISCLOSURE A process for the preparation of 8:14-dihydrothebaine froin'thebaine, in which the thebaine is reduced by heating it with at least one of the thermally decomposable cotn'g'aolinds.- selected from an aryl or substituted aryl sulphonic acid hydrazide, an alkyl or substituted alkyl sulphonic acid hydrazide, an aralkyl or substituted aralkyl sulphonic acid hydrazide or disodium azodicarboxylate, provided that when disodium azodicarboxylate is used, a proton supplying substance is present. The 8:14-dihydrothebaine may be hydrolyzed to dihydrocodeinone.

This invention relates to an improved process for the reduction of thebaine to 8: 14-dihydrothebaine, and to the 8: 14-dihydrothebaine so produced.

8:14-dihydrothebaine is an intermediate in the production of dihydrocodeinone, also known as hydrocodone, which is a well known analgesic compound produced by hydrolysis of 8:14-dihydrothebaine. The production of 8:14-dihydrothebaine by known methods as described below presents certain difiiculties and it is the object of the present invention to overcome or lessen these difliculties and to provide an improved process for the production of 8:14-dihydrothebaine thereby facilitating production of dihydrocodeinone. It is also an object of the invention to make the utilization of thebaine obtained as by-prodnet in the extraction of morphine from opium more economically attractive.

The classical known method for the reduction of thebaine to 8:14-dihydrothebaine is catalytic hydrogenation. Owing to extensive side reactions (such as hydrogenolysis of the ether bridge, and the formation of significant amounts of tetrahydrothebaine by 1:4 type of addition of hydrogen to the conjugated double bond system), however, the yield of 8:14-dihydrothebaine obtained is only 50-60% of theory. A further disadvantage of this process is that it requires a relatively pure grade of thebaine as starting material if poisoning of the hydrogenation catalyst is to be avoided.

It is known that hydrazine and certain of its derivatives are highly selective reducing agents for carbon-carbon or nitrogen-nitrogen double bonds, and a number of such reductions have been described. When hydrazine is employed, an oxidizing agent such as air or oxygen is necessary to bring about the reduction of the double bond since the true reducing agent is not hydrazine itself, but an unstable intermediate diimine NH=NH formed by oxidation of the hydrazine, thus:

The application of this procedure to the reduction of thebaine to 8:14-dihydrothebaine has recently been described by Eppenberger et al (Helv. Chim. Acta, 51 (2), 381, at 393, 1968;).

This process involved the use of gaseous oxygen, which is hazardous on an industrial scale since mixtures of hydrazine vapour and oxygen are potentially explosive, and employed a molar ratio of hydrazine to thebaine of 53:1 which is commercially unattractive.

The production of diimine by methods other than the oxidation of hydrazine has been described. One such method is the thermal decomposition of the hydrazides of aryl sulphonic acids such as benzenesulphonic acids, as follows:

The primary products of this decomposition are the aryl sulphinic acid and diimine, although in the absence of a base the benzene sulphinic acid may undergo further reaction to form sulphur compounds such as S-phenyl benzenethiosulphonate and diphenyl sulphide which can lead to a reduced yield of diimine. If, however, a base such as ethanolamine is present reaction of the benzene sulphinic acid can be prevented and the formation of these sulphur compounds largely avoided. It should be noted that this method of forming diimine does not require the use of either free hydrazine or oxygen and thus eliminates the hazard associated with the Rapoport procedure. More eflicient utilization of the hydrazine in the reduction of carbon-carbon double bonds can also be achieved by using benzene sulphonyl hydrazide as the source of diimine rather than hydrazine/oxygen.

A further method of producing diimine is by the thermal decomposition of disodium azodicarboxylate in the presence of a protic substance. Substituted acyl hydrazides, for example, chloracetyl hydrazide, can also be used to produce diimine.

According to the present invention there is provided a process for the preparation of 8.14-dihydrothebaine from thebaine, in which the thebaine is reduced by heating it with at least one of the thermally decomposable compounds selected from an aryl sulphonic acid hydrazide, an alkyl sulphonic acid hydrazide, an aralkyl sulphonic acid hydrazide or disodium azodicarboxylate is used, a proton supplying substance is present.

The process according to the invention leads to improved overall yields of dihydrocodeinone prepared from the 8:14-dihydrothebaine produced compared with those yields obtained when the first stage is the catalytic hydrogenation process or the Eppenberger procedure using bydrazine and oxygen mentioned above. It also obviates the explosion hazard associated with the use of free hydrazine and free oxygen. It is also applicable to a technical grade of thebaine which is not of sufiicient purity for use in the catalytic hydrogenation process because of the fact that it causes the hydrogenation catalyst to become rapidly poisoned. In addition, when using the hydrazine in its combined form as a sulphonyl hydrazide, it is utilized more efficiently than when employed as free hydrazine. Thus satisfactory reduction of thebaine has been obtained with 2:1 molar ratio of hydrazide to thebaine. Indeed according to the invention no particular purpose is served by increasing this molar ratio to over 4: 1.

In carrying out the process of the invention the aryl sulphonic acid may be one in which the aryl group is a benzene or naphthalene radical or a substituted benzene or substituted naphthalene radical, e.g. a monoor polyalkyl substituted benzene radical. Preferred aryl sulphonic acids are benzene and p-toluene sulphonic acid.

The hydrazide of the aryl sulphonic acid may be used in the form of a commercially available solid as in Examples 4 and 7. It may also be prepared in the form of a solution by prior reaction of hydrazine and an aryl sulphonyl chloride as in Example 2. It may also be prepared in situ as in Example 3.

An example of an alkyl sulphonic acid hydrazide which may be used is methane sulphonic acid hydrazide, but others having branched or unbranched alkyl groups may also be used. Furthermore the alkyl groups may be substituted or unsubstituted. An example of an aryl sulphonic SOzH NH:NH

acid hydrazide which may be used is benzene sulphonic acid hydrazide, but others in which the aromatic group or the alkyl group or both are substituted may also be employed. The hydrazide may be in the form of a solid, a slurry or solution which is added to the reaction mixture or may be formed in situ.

Diimine can also be produced by the thermal decomposition of disodium azodicarboxylate in the presence of a proton supplying substance. Any substance which is capable of supplying protons may be used, for example, acids, alcohols, water. Disodium azocarboxylate may be prepared from azodicarbonamide (commercially available as Genitron AC, which is a trademark) by treatment with cold aqueous concentrated sodium hydroxide solution as described in Annalen der Chemie, 271, 130 (1892).

. When a sulphonic acid hydrazide is employed the reac tion according to the invention is preferably carried out in the presence of a base, either organic or inorganic although this is not essential. If an organic base is used it should have a boiling point above that at which the diimine-producing compounds decompose. A practical lower limit in this respect is a boiling point of at least 80 C. Suitable bases which may be used include alkali metal hydroxides, ammonia, alkylamines, substituted alkylamines, aralkylamines, substituted aralkylamines and heterocyclic bases. Specific examples of such bases include sodium hydroxide solution, ethanolamine, morpholine, benzylarnine and ethylene diamine.

The reaction is also preferably carried out in the presence of a solvent. Suitable solvents are in general those which are inert to thebaine and to the reaction product. They should also have a boiling point at which the diimine-producing compound decomposes with reasonable speed. In practice a boiling point of 80 C. or over is preferred. Examples of solvents which may be used are methyl oxitol, diglyme, amyl alcohol, diethyl carbonate and morpholine. It is especially preferred to use morpholine when the source of diimine is a sulphonylhydrazide. This is because morpholine acts as both a base and solvent and gives exceptionally good results in the process of the invention.

The molar ratio of the reactants required is determined by the necessity to employ sufiicient diimine-producing compound to achieve as near total reduction of the 8:14 double bond of thebaine as practical. This can generally be achieved in accordance with the invention by using a molar ratio of diimine-producing compound to thebaine of not greater than 4: 1, and usually a ratio of 2:1 sufiices.

The 8:14-dihydrothebaine prepared by the process of the invention can be hydrolyzed to dihydrocodeinone, for example by the procedure described in Example 1 and the invention includes such hydrolysis and dihydrocodeinone so produced.

The following examples illustrate the invention:

EXAMPLE 1 '62 g. of technical thebaine alkaloid was refluxed with 150 ml. of methyl oxitol (Z-methoxyethanol) and 20 ml. of ethanolamine. 74 g. of p-toluene sulphonyl hydrazide dissolved in 150 ml. methyl oxitol was added to the refluxing solution over 15 minutes. The mixture was then refluxed for a further 1 hour. The solvent was removed by distillation under reduced pressure and water was added to the residue followed by caustic soda solution, with stirring, until the mixture was alkaline to Clayton yellow indicator paper. After cooling the crude 8: 14-dihydrothebaine was filtered off, washed and dried. Yield 58 g. (93% theory on thebaine), M.P. 162164 C. The product was over 99% pure by GLC analysis.

Hydrolysis to dihydrocodeinone The 8:14-dihydrothebaine (58 g.) was boiled under reflux with excess 2 N aqueous hydrochloric acid solution for 30 minutes. After cooling, the reaction solution was run into excess 20% aqueous sodium hydroxide solution Solubility of Percent yield p-tolune Ethanolof dihydrosulphouylne eodelnone on Solvent hydrazide added thebaine Amyl alcohol Insoluble 87. 5 15 Dirnethyl iormarnide Soluble 73 Perchloroethyleuo-. Insoluble 56 Xylene ..do 73 Amyl acetate --do B8. 7 Chlorobenzene d0 87. 1 Diglyme Soluble 79. 5 Dimethyl sulnhnxirle do Diethyl carbonate Insoluble 90. 4 Ethanolamine Soluble N 71'. 7 Pyridine do .87. 1 Morpholine .do No 94 a No product isolated.

4 A I o i containing 10% I.M.S. (66 o.p.) with stirring. e precipitated dihydrocodeinone base was filtered, washed free of caustic soda with water and dried at 60". Yield 53 g. (88% of theory one thebaine). M.P. 196-8.

In order to illustrate the effect of different solvents on the process of the invention. Example 1 was repeated using diiferent solvents. The results are shown in Table I.

TABLE I In all the above cases ethanolamine was used as the added base, except for those solvents which are themselves bases and where the use of an additional base was considered unnecessary. It will be seen that the only solvents other than methyl oxitol which gave a significantly better yield of dihydrocodeinone were diethyl carbonate and morpholine. The p-toluene sulphonylhydrazide was not completely soluble in the diethyl carbonate and therefore had to be added in the form of a slurry with the solvent, which is a disadvantage although not a serious one. The hydrazide was, however, completely soluble in the morpholine and this solvent gave the best yield of dihydrocodeinone of all those tested.

Similarly, the effect of different bases on the process of the invention was shown by repeating Example 1 using a variety of bases. The results are shown in Table 2.

TABIJE 2 None of the above bases gave significantly better results than ethanolamine, but it is interesting to note that the inorganic base sodium hydroxide gave results equal to those obtained with ethanolamine and other organic bases. Although the reaction proceeds in the complete absence of a base, the yield of dihydrocodeinone obtained is substantially reduced. Weak bases such as aniline, dimethylaniline and pyridine gave a similar result to that obtained when no base at all is present.

EXAMPLE 2 40 g. of p-toluene sulphonyl chloride was suspended in 75 ml. of methyl oxitol and cooled in an ice bath. 12 ml. of ethanolamine and 12 ml. of hydrazine hydrate (98%) were added slowly keeping the temperature below 20 C.

After the reaction was complete the mixture was warmed to dissolve all the solid present and the solution added slowly to a refluxing solution of 31 g. of technical thebaine and 10 ml. of ethanolamine in 75 ml. of methyl oxitol. The reaction mixture was worked up by the procedure described in Example 1 and yielded 27.6 g. (89% theory) of crude 8:14-dihydrothebaine, M.P. 16216 6. Qt

EXAMPLE 3 31 g. of technical thebaine, 30 m1. of ethanolamine, 75 ml. of hydrazine hydrate (98%) and 75 ml. of methyl oxitol were brought to reflux temperature in a nitrogen atmosphere. 40 g. of p-toluene sulphonylchloride dissolved in 75 ml. of methyl oxitol was then added to the refluxing solution over 15 minutes. Work-up of the reaction mixture as described in Example 1 yielded 27 g. of crude 8:14-dihydrothebaine, M.P. 162166 C.

EXAMPLE 4 31 g. of technical thebaine, ml. of ethanolamine and 75 ml. of methyl oxitol were brought to reflux temperature and 35 g. of benzene sulphonyl hydrazide (trade name Genitron BSH) in 75 ml. of methyl oxitol added over the course of minutes. Work-up of the reaction mixture as described in Example 1 yielded 28 g. of crude 8:14-dihydrothebaine, M.P. 162-164" C.

EXAMPLE 5 31 g. of technical thebaine, 10 ml. of ethanolamine and 75 ml. of toluene were brought to reflux temperature. 37 g. of p-toluene sulphonyl hydrazide dissolved in 75 ml. of warm toluene were added as in Example 1. Work-up as in Example 1 gave 28 g. of rather poor quality (M.P. 158-174 C.) crude 8:14-dihydrothebaine.

EXAMPLE 6 '31 g. of technical thebaine, 10 ml. of ethanolamine and 75 ml. of diglyme (diethylene glycol dimethyl ether) were brought to reflux temperature and 37 g. of p-toluene sulphonyl hydrazide dissolved in diglyme was added as described in Example 1. Work-up as in Example 1 yielded 28 g. of crude 8:14-dihydrothebaine, M.P. 162164 C.

EXAMPLE 7 Example 1 was repeated using a commercial grade of p-toluene sulphonyl hydrazide (trade name Unifor H) in place of pure material prepared by laboratory synthesis. The results obtained were essentially the same.

8:14-dihydrothebaine prepared according to Examples 2 to 7 could be hydrolyzed to dihydrocodeinone as described in Example 1.

EXAMPLE 8 124 g. of technical thebaine was refluxed with 300 ml. of morpholine, and a solution of 148 g. of p-toluene sulphonylhydrazide in 300 ml. of morpholine was added over the course of about 15 minutes while maintaining the reaction mixture at reflux temperature. After the addition of hydrazide was complete, the mixture was refluxed for a further period of 1 hour and the dihydrothebaine isolated as described in Example 1.

The whole of the dihydrothebaine thus obtained was hydrolyzed with two normal hydrochloric acid as in Example 1 to yield 112 g. (94% theory on thebaine) of dihydrocodeinone, M.P. 197 C.

EXAMPLE 9 To a solution of 10 g. of technical thebaine alkaloid and 10 ml. of ethanolamine in 50 ml. of boiling methyl oxitol was added two molar equivalents (referred to the thebaine) of methane sulphonylhydrazide dissolved in methyl oxitol over the course of about 30 minutes, while maintaining the reaction mixture at reflux temperature. When the addition was complete the mixture was refluxed for a further period of one hour and the dihydrothebaine isolated as in Example 1. The whole of the dihydrothebaine thus obtained was hydrolyzed as in Example 1 to give 8.2 g. (85% theory on thebaine) of good quality dihydrocodeinone.

6 EXAMPLE 10 31 g. of technical thebaine in ml. of methyl oxitol was treated at reflux temperature with a slurry of 40 g. of disodium azodicarboxylate and 100 ml. methyl oxitol added over the course of 30 minutes. When the addition was complete the reaction mixture was refluxed and stirred for a further period of 90 minutes, and the resulting dihydrothebaine then isolated as described in Example 1. The whole of the dihydrothebaine thus obtained was hydrolyzed as in Example 1 to give 21 g. (70% theory on thebaine) of dihydrocodeinone, M.P. 195 -197 C.

What is claimed is:

1. A process for the preparation of 8:14-dihydrothebaine from thebaine which comprises the step of reducing thebaine by heating it with a thermally decomposable sulphonic acid hydrazide selected from the group consisting of a monoor dicarbocyclic sulphonic acid bydrazide, an alkylated monoor dicarbocyclic sulphonic acid hydrazide, a lower alkyl sulphonic acid hydrazide, and an monocarbocyclic aryl lower alkyl sulphonic acid hydrazide.

2. The process of claim 1 wherein the reduction is carried out in the presence of an alkali metal hydroxide or a base selected from the group consisting of ammonia, a lower alkylamine, a monocarbocyclic lower alkylamine, morpholine, and pyridine.

3. A process for the preparation of 8: 14-dihydrothebaine which comprises the step of heating thebaine with p-toluene sulphonic acid hydrazide in morpholine.

4. A process as claimed in claim 1 in which the sulphonic acid hydrazide is benzene or p-toluene sulphonic acid hydrazide.

5. A process as claimed in claim 1 in which the sulphonic acid is methane sulphonic acid hydrazide.

6. A process as claimed in claim 1 in which the sulphonic acid hydrazide is prepared in situ.

7. A process as claimed in claim 2 in which the base is ethanolamine.

8. A process as claimed in claim 2 in which the base is morpholine which also acts as a solvent.

9. A process as claimed in claim 1 which is conducted in the presence of solvent which is not a base.

10. A process as claimed in claim 9 in which the solvent is methyl oxitol or diglyme.

11. A process as claimed in claim 1 in which the ratio of thermally decomposable compound to thebaine is less than or equal to 4:1.

A process as claimed in claim 11 in which the ratio is References Cited OTHER REFERENCES (lggugius et al.: Jour. Praket. Chem., vol. 58, pp. -8 Eppenberger et al.: Helv. Chim. Acta, 'vol. 51, pp. 381- DONALD G. DAUS, Primary Examiner US. Cl. X.R. 

